Select Committee on Science and Technology Written Evidence


Memorandum by the Specialist Advisory Committee on Antimicrobial Resistance (SACAR):

SURVEILLANCE, DIAGNOSTICS AND THE ROLE OF PRESCRIBING. SOME PRIORITIES IN THE FIELD OF AMR

  1.  The Seventh Report of the House of Lords Science and Technology Committee of March 1998 into resistance to antibiotics and other antimicrobial agents made a considerable impact in the United Kingdom and further afield. The report highlighted the fact that resistance to these drugs was a "major threat to public health". The report contained many recommendations, most of which are now being set in motion by the UK Government and other relevant academic and professional bodies. Amongst these recommendations was the firm suggestion that an over-arching committee to advise on problems of antimicrobial resistance and the use of these agents in both human and animal health, as suggested by the Swann Committee in 1969, should be set up. In July 2001 the Specialist Advisory Committee on Antimicrobial Resistance (SACAR) under the Chairmanship of Professor Richard Wise was convened with membership drawn from all relevant areas of the medical and allied professions, academe and industry, with observers from the devolved administrations of the UK. One of the first acts of SACAR was to draw up a list of priorities and amongst these was the realisation that surveillance of antimicrobial resistance was absolutely fundamental. Without accurate information, not only is it impossible to judge the extent of the problem of antimicrobial resistance, but it will not be possible to judge the efficacy or otherwise of any attempts that are made to control the problem in either hospitals or the community.

  2.  Antibiotics revolutionised medicine during the 20th Century, curing classical infectious diseases, safeguarding surgery and permitting immunosuppressive procedures that previously were unthinkable. Unfortunately, though, antibiotics exert a Darwinian selection for resistant bacteria and there is now international concern that the "antibiotic revolution" is under threat. 50 years ago, 95 per cent of Staphylococcus aureus isolates were susceptible to penicillin; nowadays 95 per cent are resistant. In many countries—including the UK—over 30 per cent of S. aureus isolates are now also resistant to methicillin, which was developed to overcome staphylococcal resistance to penicillin. Vancomycin retained universal activity against gram-positive cocci until 1986; but now 20 per cent of Enterococcus faecium isolates from bacteraemias in England and Wales are vancomycin resistant, as are up to 80 per cent of E. faecium from bloodstream infections in the USA. Third-generation cephalosporins seemed a panacea against gram-negative bacteria in the 1980s. Now, however, cephalosporin resistance is being reported at many centres. Carbapenems retain activity against most cephalosporin-resistant Enterobacteriaceae, but resistance is slowly emerging in some important pathogens. A few hospital isolates—mostly of non-fermentative bacteria (specifically Acinetobacter and Pseudomonas spp.)—are resistant to all reliable antibiotics. Through the 1990s there was a dearth of new antibiotics, let alone new antibiotic classes, being developed and, although new antibiotics are now being developed against gram-positive bacteria (such as MRSA and enterococci), there remains a near-total lack of new anti-gram-negative agents.

  3.  Antiviral drug development is now mirroring the speed of early development of antibacterials. Over 25 approved antivirals are available for use against such diverse viruses as HIV, hepatitis B and C, herpesviruses such as herpes simplex and cytomegalovirus, and respiratory viruses such as influenza and RSV. These drugs have had some astounding impacts on health, such as the dramatic reductions in morbidity and mortality in those infected with HIV. However, resistance to virtually all available drugs has been documented. Such resistance is encoded within the viral genome, and is associated with disease progression. More recently, transmission of drug resistant HIV has been documented, and appears to be increasing.

  4.  This document briefly addresses areas of concern identified by SACAR in relation to surveillance for, diagnosis of, and the role of prescribing in, antimicrobial resistance. SACAR is aware that the Sub-Committee for Fighting Infection will not be studying AMR as a prime area of inquiry. We have therefore limited our evidence to three areas which SACAR believe are a priority for development, particularly in the context of the CMOs strategy "Getting ahead of the Curve" and the establishment of the new Health Protection Agency.

  5.   Effectiveness of current surveillance systems. The need for improved surveillance of AMR was highlighted in the House of Lords report on this subject in 1998. Existing mechanisms for surveillance have developed in a piecemeal way in the UK. These need to be improved, developed and co-ordinated. We identify areas where additional work or new investment might be considered. We consider these at laboratory, hospital and community levels, particularly emphasising the need to build on the backbone of existing "passive surveillance" mechanisms, to develop a system of sentinel surveillance based on defined populations.

  5.1  There have been considerable developments already achieved in antimicrobial resistance surveillance, particularly through the PHLS, in line with the priorities identified in the DoH UK Antimicrobial Resistance Strategy and Action Plan published in June 2000. Strengthening of surveillance will presumably lie within the future remit of the Health Protection Agency and will require close collaboration between epidemiologists, microbiologists and clinicians. With regard to antiviral resistance, such surveillance is at an earlier stage of development.

  5.2  Generally, better understanding is required of the "drivers" for antibiotic resistance in hospitals (high intensity of antibiotic use in relatively small numbers of vulnerable/immunocompromised individuals for a range of common and "unusual" organisms) and in the community (low intensity use in large numbers of immunocompetent individuals) for common organisms, and:

    —  The interaction between them.

    —  Their relative contributions to emerging population patterns of antimicrobial resistance.

  5.3  Surveillance should improve this understanding in order to achieve action to limit the emergence and spread of resistant organisms.

  5.4  Antiviral drug development is moving apace. The principles of the emergence and transmission of antibiotic resistance mirror many of those of antiviral resistance. We have an opportunity to set in place appropriate laboratory, clinical and epidemiological structures to monitor and limit spread of these viruses, and therefore avoid the mistakes made with antibiotics.

6.  IMPROVING SURVEILLANCE

6.1  Laboratory issues

  Much surveillance of resistance depends on the collection of routine susceptibility data from diagnostic laboratories. These data are much less comprehensive than those available in other developed countries. Specifically:

    —  Isolates of Enterobacteriaceae (the largest group of gram-negative bacteria) are often not identified to species level in the UK, except from bacteraemias. This is inadequate because the relative proportions of different gram-negative pathogens are changing among hospital patients and because some species are more prone to develop resistance than others. Thus, observed shifts in resistance prevalence may reflect either a shift in species prevalence or a shift in resistance prevalence within species. These possibilities are indistinguishable if bacteria are not identified properly.

    —  Isolates are tested with too few antibiotics. Most UK laboratories test circa six drugs per isolate (the maximum number of discs that conveniently fit on a standard nine cm petri dish). In France 16 discs would be tested. Modern automated susceptibility testing systems test circa 18-23 drugs per isolate. If bacteria have been identified to species level and sufficient drugs are tested, resistance mechanisms can often be inferred from phenotypes, aiding therapeutic choice and resistance surveillance.

    —  Isolates from different places are tested with different antibiotics. This again reflects isolates being tested with few antibiotics. If laboratories tested a wider range of agents it would be possible to agree a standard core set to be included by all sites.

    —  Antiviral resistance data is obtained from a few specialist laboratories at present. However, there are already a variety of methods used, especially for HIV resistance, with a lack of standardisation of procedures and interpretation.

  Methodology. Adoption of BSAC disc method has improved standardisation of disc testing in the UK. Nevertheless, this improvement is compromised by lack of species identification and by the limited ranges of antibiotics tested at most labs. Further improvement could best be achieved by adoption of automated testing. These provide I/D, standardisation and use wide panels of antibiotics. Their "expert systems" filter the results, identifying unusual profiles that deserve reference laboratory investigation. Moves towards standardisation of antiviral resistance assays, interpretation and reporting should be made as a matter of urgency.

6.1.1  Molecular characterisation of resistance

  Detailed investigation by a reference, specialist or academic laboratory is warranted where unexpected resistances are found at a diagnostic laboratory, eg:

    —  Resistance in a species that was previously always susceptible.

    —  Resistance to unusual combinations of analogues within a drug family.

    —  Where resistance is increasing dramatically, either locally or nationally.

  There is a need to ensure appropriate co-operation and co-ordination of expertise currently within NHS, PHLS and academic institutions (especially with the changes being made consequent on the formation of the HPA) in order to deliver such analyses. The precise investigations vary with the particular situation but typically include sequencing of resistance gene(s) and identification of its location (integron, transposon, plasmid or chromosome), also biochemical characterisation of the gene product, which may be an antibiotic degrading enzyme, efflux system or target modifying activity. Also vital is determination of whether resistance is encoded by a transferable element or not. If multiple resistant isolates are found it is important to identify whether a single resistant strain has disseminated among patients, whether a promiscuous resistance plasmid has transferred among strains or whether they represent independent evolution. Application of phylogenetic approaches to sequence based resistance testing of viruses allows for identification of epidemiological loci of transmission events.

  The selection of appropriate isolates for these studies can be much-strengthened by improved reporting of routine data. Molecular investigation of resistance itself depends on the recruitment and retention of appropriate staff in what has recently often been seen as an unfashionable area of molecular microbiology.

  6.1.2  Aside from the problems outlined as above, existing laboratory-based surveillance includes very limited data on the source of tested organisms or the clinical basis for testing. Thus data cannot be related to any population denominator (within or outside hospitals) to estimate, for example, changing prevalence of resistance over time. Furthermore, the bacteria that reach laboratories may be a very biased sample of circulating organisms which further limits our understanding of true patterns of resistance in the population. Thus clinically based sentinel surveillance schemes are important. Where the costs of resistance testing are large (eg HIV@ £250/test) efforts must be made to capture routinely acquired laboratory results and full associated clinical data within nationally based databases, since drug therapy information is vital to understand apparent trends in resistance observed.

6.2  Hospital surveillance

  6.2.1  Improved information is required concerning hospital prescribing (numbers, type and reason for prescribing). At present, considerable investment is being planned for development of Information Technology for the NHS. A national prescribing database for hospitals (and associated IT) would be a very important element in understanding AMR. This should be linkable on to data on resistance patterns in hospitals (improved as above).

  6.2.2  In the shorter term, we are aware that there are commercially funded systems recording in-patient prescribing (eg IMS, and DMD). While these systems collect data from some NHS hospitals, we understand that these data are not widely available to the NHS. The possibility of using IMS/DMD databases for correlating prescribing patterns in hospitals with antibiotic resistance patterns in sentinel hospitals should be considered.

  6.2.3  Strategies for monitoring antimicrobial resistance in hospital should be closely co-ordinated with surveillance activities to monitor health care associated infections and related control programmes.

6.3  Community surveillance

  6.3.1  Surveillance in patterns of resistance in the community is restricted by:

    —  The considerable bias in sampling specimens sent for microbiological tests reaching the laboratory.

    —  The lack of population denominators.

    —  The limitations of PACT data on primary care prescribing (no data on reasons for prescribing).

    —  The difficulties in identifying the source of specimens (hospital or community) in RGSD.

    —  Poor understanding of the extent to which resistance in the community is initially acquired in hospital or outside and vice versa.

    —  The ability to identify low frequency events, such as the emergence of a novel resistance.

  6.3.2  Existing surveillance systems in the community require enhancement and investment in order to provide timely information on emerging resistance and to monitor trends in susceptibility of common bacterial infections. Linkage of microbiological data to appropriate IT systems on prescribing is essential, to inform the relationship between prescribing and resistance over time. These data are needed as a source of intelligence for public health intervention to reduce or alter inappropriate prescribing. It is important to note that prescribing inappropriate antibiotics, for example those unlikely to be active, is as much a problem as general over-prescribing.

  6.3.3  The absence of good denominator information and the biases inherent in the routine specimens collected by the laboratories indicate the need for investment in more detailed (in-depth) surveillance to improve understanding of the drivers and transmission dynamics of antimicrobial resistance both inside and outside hospitals, and the interactions between them.

  6.3.4  As part of its activity SACAR is considering the need for, and design of, a national "sentinel surveillance system" based on a defined population. Such a sentinel system would collect a "minimum data-set" on laboratory forms including source of specimen (GP/hospital and hospital length of stay), reason for and site of testing and past antibiotic exposure. It would attempt to systematically sample cases in both hospital and community to provide adequate denominators in both settings. Such a system would aim to identify drivers in hospital and community and the link between the two. (An example of the establishment of such a national "active surveillance system" is the DoH funded Unlinked Anonymous HIV Prevalence Monitoring Programme managed by the PHLS).

7.  INFORMATION TECHNOLOGY

  7.1  The establishment of adequate surveillance of hospital prescribing and links to community will require appropriate investment in information technology (see 6.2.1). A particularly important consideration is the need for data linkage between hospital and community, laboratory data and prescribing data.

  An effective backbone of surveillance would need the following linked data-sets:

    —  Hospital prescribing (by clinical indication).

    —  Hospital antibiotic resistance (by site and organism).

    —  Community prescribing (by clinical indication).

    —  Community resistance (by site and organism).

  7.2  The increasing use of gene sequencing to identify drug resistance associated mutations has generated huge amounts of data, invaluable for exploring emergence of hitherto unrecognised drug resistance patterns. With regard to HIV, for instance, there is enormous potential in compiling UK data to allow construction of algorithms for the direct benefit of the NHS. New bioinformatic approaches are required to maximise such benefit, and multi-agency collaboration is required to achieve this. Similar datasets will be generated for other organisms. It is essential that such "raw" data, from which laboratory interpretation is made, is included within data storage and acquisition for surveillance purposes, in view of the above issues and also since this represents the molecular archaeology of circulating microorganisms within the country as a whole.

8.  SURVEILLANCE OF SERIOUS SEQUELAE OF UNTREATED INFECTION

  One adverse outcome of reduced antimicrobial prescribing might be the increase in serious sequelae of untreated infection (eg Quinsy, community-acquired pneumonia, glomerular nephritis, rheumatic fever) for which hospital surveillance might be the most appropriate.

9.  FUNGI

  We have focused on antibiotic and antiviral resistance but increasing use of over-the-counter antifungals (eg fluconazole, clotrimazole) indicates the need for development of surveillance of resistance in the medium term.

October 2002


 
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